RESUMEN
Two series of 3,5-disubstituted isoxazoles (6a-e) and 1,4-disubstituted triazoles (8a-e) derivatives have been synthesized from tyrosol (1), a natural phenolic compound, detected in several natural sources such as olive oil, and well-known by its wide spectrum of biological activities. Copper-catalyzed microwave-assisted 1,3-dipolar cycloaddition reactions between tyrosol-alkyne derivative 2 and two series of aryl nitrile oxides (5a-e) and azides (7a-e) regiospecifically afforded 3,5-disubstituted isoxazoles (6a-e) and 1,4-triazole derivatives (8a-e), respectively in quantitative yields. Synthesized compounds were purified and characterized by spectroscopic means including 1D and 2D NMR techniques and HRMS analysis. The newly prepared hybrid molecules have been evaluated for their anticancer and hemolytic activities. Results showed that most derivatives displayed significant antiproliferative activity against human glioblastoma cancer cells (U87) in a dose-dependent manner. Compounds 6d (IC50 = 15.2 ± 1.0 µg/mL) and 8e (IC50 = 21.0 ± 0.9 µg/mL) exhibited more potent anticancer activity. Moreover, most derivatives displayed low hemolytic activity, even at higher concentrations which suggested that these classes of compounds are suitable candidates for further in vivo investigations. The obtained results allow us to consider the newly synthesized isoxazole- and triazole-linked tyrosol derivatives as promising scaffolds for the development of effective anticancer agents.
Asunto(s)
Antineoplásicos/farmacología , Glioblastoma/tratamiento farmacológico , Isoxazoles/farmacología , Alcohol Feniletílico/análogos & derivados , Triazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Glioblastoma/patología , Humanos , Isoxazoles/química , Estructura Molecular , Alcohol Feniletílico/química , Alcohol Feniletílico/farmacología , Relación Estructura-Actividad , Triazoles/química , Células Tumorales CultivadasRESUMEN
In this work, 40 analogs with a natural maslinic acid core (from Olea europaea L.) and various aromatic azides were synthesized. A regiospecific, facile and practical synthesis of 1,5-triazolyl derivatives by Ru(II)-catalyzed azide-alkyne cycloaddition (RuAAC), and mono-, bis- and tri-1,4-triazolyl derivatives by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was described. All the reactions were assisted by microwave irradiation avoiding toxic reagents and solvents. The new products were obtained from the reaction mixture by simple purification in almost quantitative yields and the reaction times were in general shorter than those reported in the literature. Their chemical structures were elucidated on the basis of extensive spectroscopic methods including ESI-HRMS, 1D and 2D-NMR. Most of the compounds were evaluated for their anti-inflammatory activity using LPS-stimulated human peripheral blood mononuclear cells (PBMCs) and antiproliferative effects towards cultured murine EMT-6 (Breast) and human SW480 (colon) cancer cell lines.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Microondas , Triazoles/farmacología , Triterpenos/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/biosíntesis , Leucocitos Mononucleares/efectos de los fármacos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Relación Estructura-Actividad , Triazoles/química , Triterpenos/síntesis química , Triterpenos/química , Células Tumorales CultivadasRESUMEN
In late December 2019, a novel coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), escaped the animal-human interface and emerged as an ongoing global pandemic with severe flu-like illness, commonly known as coronavirus disease 2019 (COVID-19). In this study, a molecular docking study was carried out for seventeen (17) structural analogues prepared from natural maslinic and oleanolic acids, screened against SARS-CoV-2 main protease. Furthermore, we experimentally validated the virtual data by measuring the half-maximal cytotoxic and inhibitory concentrations of each compound. Interestingly, the chlorinated isoxazole linked maslinic acid (compound 17) showed promising antiviral activity at micromolar non-toxic concentrations. Thoughtfully, we showed that compound 17 mainly impairs the viral replication of SARS-CoV-2. Furthermore, a very promising SAR study for the examined compounds was concluded, which could be used by medicinal chemists in the near future for the design and synthesis of potential anti-SARS-CoV-2 candidates. Our results could be very promising for performing further additional in vitro and in vivo studies on the tested compound (17) before further licensing for COVID-19 treatment.
RESUMEN
In this article, we report an effective procedure for the selective isolation of oleanolic acid 1 and maslinic acid 2 (3.4 and 8.5mg/g DW, respectively) from pomace olive (Olea europaea L.) using an ultrasonic bath, and the synthesis of a series of new triterpenic acid esters. The compounds were characterized by their spectral data and were evaluated for their antimicrobial activity. Among the compounds tested, those having sulfur and chlorine atoms were found to be antibacterial. They showed activity against two Gram-positive bacteria Staphylococcus aureus and Enterococcus faecalis and two Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa (MICs within a range of 5-25µg/mL). The fungus Penicillium italicum was found to be the most sensitive to both sulfur derivatives: (3ß)-3-((thiophene-2-carbonyl)oxy)-olean-12-en-28-oic acid (1a) (IZ=22mm) and (2α,3ß-2,3-bis((thiophene-2-carbonyl)oxy)olean-12-en-28-oic acid (2a) (IZ=24mm).